Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/51—Nanocapsules; Nanoparticles
  • A61K9/5107—Excipients; Inactive ingredients
  • A61K9/513—Organic macromolecular compounds; Dendrimers
  • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/23—Calcitonins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/28—Insulins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
  • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
  • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
  • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
  • A61K47/6931—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
  • A61K47/6933—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained by reactions only involving carbon to carbon, e.g. poly(meth)acrylate, polystyrene, polyvinylpyrrolidone or polyvinylalcohol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S977/00—Nanotechnology
  • Y10S977/70—Nanostructure
  • Y10S977/773—Nanoparticle, i.e. structure having three dimensions of 100 nm or less
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S977/00—Nanotechnology
  • Y10S977/84—Manufacture, treatment, or detection of nanostructure
  • Y10S977/90—Manufacture, treatment, or detection of nanostructure having step or means utilizing mechanical or thermal property, e.g. pressure, heat
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S977/00—Nanotechnology
  • Y10S977/902—Specified use of nanostructure
  • Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
  • Y10S977/915—Therapeutic or pharmaceutical composition

Definitions

• the invention relates to nanoparticles containing an active ingredient and a polyketal tartaric acid amide, which are suitable as drug carriers for active ingredients, in particular for peptides or proteins.
• biodegradable drug delivery systems as specified in US 4,093,709, the active ingredient is dispersed in a biodegradable polymer which releases the active ingredient upon degradation.
• Typical biodegradable polymers that are mostly investigated according to the prior art are homo- and copolyesters, in particular lactic and glycolic acid, as described in US Pat. Nos. 3,773,919 and 3,297,033. Disadvantages are u. a. the poorly controllable swellability of the polyester in the physiological environment and the associated complex mechanism of drug release. In addition, only a low to moderate release rate is generally brought about after a substantial "initial burst".
• EP 0 514 790 already describes polyketal tartaric acid amides. However, the processes described there fail to produce nanoparticles that contain an active ingredient.
• oral administration forms should also promote the absorption of the active ingredient through the intestinal wall.
• a targeted release in the intestinal lumen from capsules that are enteric-resistant prevents acidic hydrolysis in the stomach, but can lead to peptide and protein active ingredients being subject to degradation through digestion.
• Examples of such release forms are capsules made of polyacrylic derivatives with pH-dependent coatings (Rubinstein et al. Int. J. Pharm. 30, 95-99, 1986) and capsules with azoaromatic film coatings that are broken down bacterially (Saffran et al. Science, 233, 1081-1084, 1986).
• the object of the present invention is to produce nanoparticles which are biocompatible and degradable and are suitable as carriers, in particular for peptide and protein active ingredients, and serve as a release and transport system.
• nanoparticles can be produced from polyketal tartaric acid amides of the formula I and active ingredients which are suitable for use as transport and release systems for the application of medicaments.
• the invention therefore relates to nanoparticles containing an active ingredient and a polyketal tartaric acid amide which essentially contains at least 95 mol% of recurring structural units of the formula I, where R1 for the rest of formula II stands, X stands for -NH-, and R2 is straight-chain or branched alkyl or cycloalkyl, which can be substituted by one or more inert radicals.
• inert radical is understood to mean substituents which do not react with one another under the production and processing conditions of the polyketalartaric acid amides or are prevented from reacting with one another by protective groups.
• Inert radicals can be, for example, inorganic radicals, such as halogen, or it can be organic radicals, such as alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, or dialkylaminoalkyl.
• Functional groups that are prevented from reacting by protective groups are, for example, amino or hydroxy.
• active ingredient is understood to mean active ingredients based on carbohydrates, peptides and proteins, for example insulin, calcitonin or buserelin.
• Nanoparticles are spherical bodies with a diameter of 10 to 1000 nm, preferably from 50 to 800 nm, in particular from 200 to 600 nm.
• dimethyl 2,3-isopropylidene tartarate is used with one or more of the diamines, of the formula IV H2N - R2 - NH2 (IV) around, where R2 has the meaning given above.
• the molecular weight of the resulting polyketal tartaric acid amides can be controlled, inter alia, by selecting the proportions from A to B. These selection criteria are known to the person skilled in the field of polycondensation.
• Examples of suitable diamines of the formula IV are 1,6-diaminohexane, 1,8-diaminooctane, trans-1,4-diaminocyclohexane or 1,12-diaminododecane.
• the condensation of the components described above is generally carried out in solution.
• the monomeric compounds to be reacted with one another are generally dissolved in an organic solvent.
• the organic solvent preferably contains at least one solvent, e.g. B. N-methyl-2-pyrrolidone or toluene.
• the synthesis of the polyketal tartaric acid amides of the formula I takes place in two stages, starting from tartaric acid and diamine.
• the first stage of dimethyl isopropylidene tartar can be prepared directly from tartaric acid and 2,2-dimethoxypropane without isolation of the intermediate isopropylidene tartaric acid.
• High-boiling solvents such as N-methylpyrrolidone or toluene are used to carry out the solution polymerization.
• the reaction is carried out, for example, from 80 to 140 ° C.
• the methanol formed is distilled off azeotropically or removed by introducing an N2 stream.
• melt condensation which can be carried out with the tartaric acid methyl esters despite the ketal groups and which leads to uniform products in an elegant and simple manner, is a particular advantage.
• the reactants are first stirred for 1 to 6 hours (h) at temperatures of 30 to 80 ° C. in order to escape one of the monomer components to prevent.
• the mixture is then heated to 80 to 120 ° C. for 8 to 16 h under reduced pressure.
• the polymers are usually dissolved in dichloromethane and precipitated in suitable precipitants such as diisopropyl ether.
• the molecular weight of the polymer and thus also the viscosity of the reaction mixture increase.
• Molecular weights of 1,000 to 100,000 are achieved, preferably 5,000 to 40,000.
• Viscosities of more than 0.1 dl ⁇ g ⁇ 1 (Staudinger index, dimethylformamide, 25 ° C.) are generally achieved.
• the structure of the polyketal tartaric acid amides enables good control of the degradability, since hydrolysis can take place both via the side groups and via the main chain.
• the rigid structure of the polyketal tartaric acid amides obtained is caused by the ketal ring of tartaric acid and gives the polymers the property, despite the hydrogen-bond-forming amide structure, of forming solid, water-insoluble forms, especially particles, which can even take up water-soluble components such as proteins without the form in soft, sticky aggregates pass over, as is often observed with other polyamides. It is even possible to reduce the size of the particles down to the nanometer range while maintaining the properties required for transport systems, in particular the high loading capacity, the low tendency to aggregate in solution and the stability of the dried nanoparticles and their resuspendability. In addition, these nanoparticles can take up other components with very hydrophilic groups such as polyamines, polyhydroxycarboxylic acids and polymeric fluorescent markers without losing their defined particulate form.
• the nanoparticles are produced by coacervation or spray drying.
• polyketal tartaric acid amides and active ingredients are dissolved separately, combined into a homogeneous solution and precipitated into nanoparticles in a precipitant.
• the active ingredient is included in the polymer matrix.
• solvents and precipitants are used, which do not affect the active ingredient e.g. lead through denaturation.
• the volume of the droplets obtained is 0.0005 to 0.01 ml, preferably 0.001 to 0.005 ml.
• the initial charge is stirred rapidly, the stirrer rotating at about 1000 revolutions per minute (1000 rpm).
• the nanoparticle fraction is resuspended in water, optionally with the addition of a suspension aid (maximum 1%), centrifuged and freeze-dried.
• the dried nanoparticles obtained in this way can be resuspended well. It has been shown that the polyketal tartaric acid amides of the formula I can be used to carry out the generally particularly difficult step of isolating the nanoparticles from the suspension, in particular if the conditions described are observed. In order to avoid the formation of aggregates, the solvents and precipitants used should not be cooled and the stirring speed should be well below 20,000 rpm.
• the size of the nanoparticles can be adjusted via the concentration of the polymer solution and the volume ratio of solvent to precipitant.
• vitamin B12 vitamin B12 analogs such as cyanocobalamin, aquocobalamin, adensosylcobalamin, methylcobalamin, hydroxycobalamin, cyanocobalamin carbanalide, 5-O-methylbenzylcobalamin, desdimethyl, monoethylamide and methylamide analogues of these compounds, analogs and homologues of cobamamide, -Deoxyadenosylcobalamin, chlorocobalamin, sulfitocobalamin, nitrocobalamin, thiocyanatocobalamin, benzimidazole derivatives, adenosylcyanocobalamin, cobalaminlactone, cobalamin lactam and the anilide, ethyl amide, propionamide, monocarboxylic acid and dicarbipidyl hydr
• the coupling groups used are polyvinylamine or polylysine, which form covalent bonds with free carboxyl or amine groups on the surface of the nanoparticle.
• the ligand and the coupling group can also be connected to one another via a spacer compound such as an alkyl radical having 1 to 18 carbon atoms, preferably 4 to 8 carbon atoms.
• Vitamin B12 monocarboxylic acid is preferably coupled to the nanoparticles via an adipyl hydrazide.
• polyamines such as polyvinylamine or polylysine
• polyhydroxy acids such as polyaspartic acid
• the polyketal tartaric acid amides to be sprayed are used in concentrations of 0.2 to 5%, preferably 0.5 to 1.5%, in pure solvents such as acetone, methanol, ethanol or dioxane and in mixtures of these components with little addition, if appropriate set by water.
• This one Polymer solutions are the active ingredients in concentrations of 1 to 60%, preferably 4 to 25% (w / w based on polyketal tartaric acid amide), optionally FITC-labeled polymer (0.2 to 5%), or suspension aids in the range of 1 to 20% , preferably from 2 to 10%, and basic polymer in the range from 0.5 to 30%, in particular 1 to 10%, added.
• the solution to be sprayed from polymer, active substance and optionally further additives must have a specific viscosity of 0.2 to 3.5, in particular 0.3 to 2.0.
• the resulting nanoparticles are collected on a fine-mesh screen fabric (nylon fabric with a pore size of 0.010 mm).
• the particle size is from 10 nm to 1000 nm, the mean value is generally well below 600 nm.
• the particles are kept for 2 to 8 hours after spraying under reduced pressure.
• the yield is 25 to 80%, usually more than 50%.
• Suitable filters have a pore size of 0.2 ⁇ m to 0.8 ⁇ m, preferably 0.45 ⁇ m.
• Suitable membranes consist, for example, of cellulose acetate.
• the particle size is determined by means of photon correlation spectroscopy (PCS), aerosol spectroscopy and electron microscopy (REM) (JP Fischer, Progress in Colloid and Polymer Science, 77, pages 180-194, 1988), if available, the surface basicity of the nanoparticles is determined using polyelectrolyte titration (streaming current detector, SCD), the fluorescence content determined spectroscopically and the active ingredient content and release chromatographically.
• SCD polyelectrolyte titration
• the nanoparticles obtained have a narrow size distribution.
• the non-uniformity of the nanoparticles obtained (dw / dn) is from 1.1 to 2.0, in particular 1.15 to 1.5.
• the nanoparticles are also suitable for calibration purposes in scanning electron microscopy or for detecting the distribution of active substances in the body of animals or humans after oral administration if the nanoparticles contain a fluorescent or radioactive marker.
• the biodegradable particle disintegrates and is excreted by the body.
• 1,6-Diaminohexane is melted and weighed in an exact molar ratio (7.814 g, 60 mmol) to dimethyl-2,3-O-isopropylidene-D, L-tartrate (13.094 g, 60 mmol). After adding 15 ml of N-methylpyrrolidone, the mixture is stirred at 120 ° C. under N2 for 4 days. During this time, 20 ml of toluene are added 5 times each and distilled off together with the methanol formed. After adding dichloromethane, it is precipitated twice in ice-cooled diisopropyl ether. The polymer formed is dried under reduced pressure at 40 ° C to constant weight. Yield: 13.7 g Softening point T g : 96 ° C
• the suspension is centrifuged at 15,000 rpm for 15 min, the supernatant is decanted and the particle fraction is taken up in 10 ml of water.
• the suspension is centrifuged again under the conditions mentioned above and freeze-dried after resuspension. Yield: 48% Particle diameter: less than 500 nm (according to SEM)
• a 0.5% solution is sprayed, which consists of three individual solutions, which are combined in the order 1 to 3:
• Solution 1 280 mg polymer (example 3), dissolved in 55 ml of methanol Solution 2: 60 mg polylysine dissolved in 10 ml of methanol Solution 3: 40 mg insulin dissolved in 10 ml of methanol and 0.040 ml of 1N HCl
• Solution 1 25 mg polymer (according to Example 3) dissolved in 10.4 ml of methanol
• Solution 2 1.56 mg insulin dissolved in 1.04 ml of methanol and 0.01 ml of 1N HCl
• a monocarboxyl derivative of vitamin B12 is produced by acid hydrolysis and purification using an ion exchanger such as DOWEX® AGI-X8 (EP 0 220 030). 50 mg of the monocarboxylic acid obtained from vitamin B12 are dissolved in 500 ⁇ l of DMSO and then 15 ⁇ l of diisopropylethylamine are added. The solution is stirred at room temperature under N2 protective gas. A solution of 18 mg of TSTU (O- (N-succinimidyl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate) in 100 ⁇ l DMF is added to this solution. The reaction solution is allowed to react at room temperature for 20 minutes.
• TSTU O- (N-succinimidyl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate
• the reaction solution is diluted with 25 ml of distilled water and filtered through a 0.45 ⁇ m filter (Schleicher & Schuell single-use filtration unit, cellulose acetate membrane) and using a preparative reverse-phase high-pressure liquid chromatography column (RP-HPLC column; Vydac 218TP1010; mobile phase A: 0.1% trifluoroacetic acid (TFA) in distilled water, mobile phase B: 0.1% TFA in acetonitrile: water (70:30), flow: 4 ml / min) separated.
• RP-HPLC column Vydac 218TP101010
• mobile phase A 0.1% trifluoroacetic acid (TFA) in distilled water
• mobile phase B 0.1% TFA in acetonitrile: water (70:30)
• flow 4 ml / min
• nanoparticles prepared according to Example 4, are suspended in 10 ml of distilled water and through a disposable filter with a cellulose acetate membrane and the pore size of 0.45 microns filtered. Yield: 385 mg, average particle diameter 320 nm.
• the suspension is diluted with 15 ml of distilled water and the cleaning is carried out by repeated filtrations (0.22 ⁇ m cellulose acetate membrane, 0.8 bar (N2) and medium stirring speed) with 0.5% polyvinylpyrrolidone 90 (BASF) (PVP90) dissolved in water as Wash solution at a temperature of 2 to 8 ° C.
• the cleaning can be ended when the filtrate no longer has a weak red color.
• the suspension is freeze-dried and stored at 2 to 8 ° C until further use.
• the content of vitamin B12 on the surface of the nanoparticles is determined by "electron spectroscopy for chemical application" with 0.03 atomic percent cobalt.
• Adipic acid dihydrazide and vitamin B12 monocarboxylic acid are reacted analogously to Example 7.
• the purification is carried out by high pressure liquid chromatography analogous to example 7.
• vitamin B12 monocarboxylic acid adipyl hydrazide (as prepared above) are dissolved in 100 ⁇ l of distilled water and added to the above reaction solution. The mixture is stirred at room temperature for 6 hours. Then the suspension is distilled with 15 ml. Diluted water and cleaning is carried out by repeated filtration (0.22 ⁇ m Millipore filter, 0.8 bar N2 and medium stirring speed) with 0.5% PVP90 as a washing solution at 2 to 8 ° C. The retentate is lyophilized and stored at 2 to 8 ° C.
• anhydroaspartic acid 140 g are suspended in 800 ml of water. 350 ml of 2 molar sodium hydroxide solution are added dropwise over a period of 5 hours in such a way that the pH does not rise above 9.5 +/- 0.1.
• the reaction solution is filtered and the pH of the filtrate is adjusted to 7.
• the polyaspartic acid contained in the filtrate is purified several times by ultrafiltration and then lyophilized.
• Solution 1 1 g polymer (according to Example 3) 12 mg polyvinylamine 12 mg polyaspartic acid (as prepared above)
• Solution 2 60 mg insulin
• the diameter of the resuspended and then filtered nanoparticles is 160 nm (according to PCS).

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